The chemical and medical literature describes compounds that are antimicrobial, i.e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria. For example, such antibacterial agents are described in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Greyson, ed., 1982), The Molecular Basis of Antibiotic Action, 2d ed. (E. Gale, et al., 1981), Recent Research Developments in Antimicrobial Agents & Chemotherapy (S. G. Pandalai, ed., 2001), Quinolone Antimicrobial Agents (J. S. Wolfson, D. C. Hooper, eds., 1989), and Antibiotics and Chemotherapy, 7th edn. (F. O'Grady, H. P. Lambert, R. G. Finch, D. Greenwood, M. Dedicoat, 1997).
The mechanisms of action of these antibacterial agents vary. However, they may function in one or more ways including: by inhibiting cell wall synthesis or repair; by altering cell wall or membrane permeability; by inhibiting or altering protein synthesis; by inhibiting the synthesis of nucleic acids or by inhibition of folate metabolism. For example, beta-lactam antibacterial agents act through inhibiting essential penicillin binding proteins (PBPs) in bacteria, which are essential for cell wall synthesis. As another example, quinolones act, at least in part by inhibiting synthesis of DNA, thus preventing the cell from replicating.
The pharmacological characteristics of antimicrobial agents, and their suitability for any given clinical use, vary. For example, the classes of antimicrobial agents (and members within a class) may vary in 1) their relative efficacy against different types of microorganisms, 2) their frequency and rate of development of microbial resistance and 3) their pharmacological characteristics, such as their bioavailability and biodistribution. Accordingly, selection of an appropriate antimicrobial agent in a given clinical situation requires analysis of many factors, including the type of organism involved, the desired method of administration, the location of the infection to be treated and other considerations.
However, many such attempts to produce improved antimicrobial agents yield equivocal results. Indeed, few antimicrobial agents have been produced that are truly clinically acceptable in terms of their spectrum of antimicrobial activity, avoidance of microbial resistance, pharmacology, and toxicology. Thus, there is a continuing need for antimicrobial agents that are effective against resistant microbes. This need has been highlighted in the relevant literature. See, for example, C. F. Amábile-Cuevas, “New Antibiotics and New Resistance”, American Scientist, vol. 91, 138-149 (March-April 2003) (noting that for nearly twenty years, until the late 1990s, “not a single truly new antibiotic was introduced into clinical use”, while “resistance keeps evolving, and drugs are rapidly losing their efficacy, resulting in increased treatment costs, loss of labor time and, of course worst of all, lost lives.”).
Examples of bacterial infections resistant to antibiotic therapy have been reported in the past; they are now a significant threat to public health. For example, methicillin-resistant Staphylococcus aureus (MRSA) is a type of bacterium that is resistant to certain antibiotics. These antibiotics include methicillin, amoxicillin, and ciprofloxacin. Staphylococcus infections, such as those with MRSA, have a plurality of origins. They occur most frequently among persons in hospitals and healthcare facilities, such as nursing homes and dialysis centers, who have weakened immune systems. These infections, however, are not limited to exposure to the environment in healthcare facilities or medical procedures such as dialysis, surgery, and catheters, but they are also acquired by the population at large, hence the term community-associated MRSA. The development of microbial resistance (perhaps as a result of the extensive use of antibacterial agents) is of increasing concern in medical science. “Resistance” can be defined as the existence of organisms, within a population of a given microbial species, that are considerably less susceptible to the action of a given antimicrobial agent. This resistance is of particular concern in environments such as hospitals and nursing homes, where relatively high rates of infection and extensive use of antibacterial agents are common. See, e.g., W. Sanders, Jr., et al., “Inducible Beta-lactamases: Clinical and Epidemiologic Implications for the Use of Newer Cephalosporins”, Review of Infectious Diseases, p. 830 (1988).
Pathogenic bacteria are known to acquire resistance via several distinct mechanisms including inactivation of the antibiotic by bacterial enzymes (e.g., β-lactamases hydrolyzing penicillin and cephalosporins), whether these enzymes are encoded by genes native to the organism or encoded by genes acquired through transfer from an external source (e.g., methicillin-resistance in Staphylococcus aureus); removal of the antibiotic using efflux pumps; modification of the target of the antibiotic via mutation and genetic recombination (e.g., penicillin-resistance in Neiserria gonorrhoeae). There are certain Gram-positive pathogens, such as vancomycin-resistant Enterococcus faecium, which are resistant to virtually all commercially available antibiotics.
Hence existing antibacterial agents have limited capacity in overcoming the threat of resistance. Thus it would be advantageous to provide new antibacterial agents that can be used against resistant microbes.
The present invention includes pyrazole compounds and derivatives thereof; the use of said pyrazole compounds as inhibitors of bacterial growth; their use for the treatment of bacterial infection; and the preparation of pharmaceutical compositions for the treatment of bacterial infection. Compounds according to the present invention and derivatives thereof can also be used as reference compounds in assays to assess antibacterial characteristics in light of one or more factors concerning bacterial activity, such as bacterial growth inhibition, toxicity, bioavailability, and protein binding capability.